A B S T R A C T PurposeTo determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and MethodsPatients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m 2 ) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received Ն 6 cycles of oral azacitidine. ResultsOverall, 41 patients received SC and oral azacitidine (MDSs, n ϭ 29; CMML, n ϭ 4; AML, n ϭ 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. ConclusionOral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

Summary Background Safe and effective treatments are urgently needed for patients with relapsed/refractory acute myeloid leukaemia (AML). We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed/refractory AML. Methods VALOR was a phase 3, double-blind, placebo-controlled trial conducted at 101 international sites. Patients were randomised 1:1 to vosaroxin (90 mg/m2 IV days 1,4) plus cytarabine (1 g/m2 IV days 1–5) (vos/cyt) or placebo plus cytarabine (pla/cyt) using a permuted block procedure stratified by disease status, age, and geographic location. All participants were blind to treatment assignment. Primary endpoints were overall survival (OS) and 30- and 60-day mortality. Efficacy analyses were by intention-to-treat; safety analyses included all treated patients. This study is registered at clinicaltrials.gov (NCT01191801). Findings Between December 2010 and September 2013, 711 patients were randomised to vos/cyt (n=356) or pla/cyt (n=355). Median OS was 7·5 months with vos/cyt and 6·1 months with pla/cyt (hazard ratio 0·87; unstratified log-rank p=0·061; stratified p=0·0241) and was supported by a sensitivity analysis censoring for subsequent transplant (6·7 and 5·3 months; p=0·0243). Complete remission (CR) rate was higher with vos/cyt vs pla/cyt (30·1% vs 16·3%, p<0·0001). Early mortality rates were equivalent (vos/cyt vs pla/cyt: 30-day, 7·9% vs 6·6%; 60-day, 19·7% vs 19·4%). Treatment-related deaths occurred at any time in 18 patients (5·1%) with vos/cyt and 8 (2·3%) with pla/cyt. Grade ≥3 adverse events more frequent with vos/cyt included febrile neutropenia (167/355 [47%] vs 117/350 [33%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Interpretation Addition of vosaroxin to cytarabine prolonged survival in patients with relapsed/refractory AML, increasing CR rates with equivalent early mortality. These results support vos/cyt as an option for salvage therapy in AML patients. Funding Sunesis Pharmaceuticals

Background: Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor (BTKi) with potent in vitro inhibitory activity against both wild type and C481S-mutated BTK, the most common mutation detected in patients (pts) with CLL relapsing on treatment with covalent BTKi (cBTKi). Methods: This is an open-label, modified 3+3 dose-escalation, cohort expansion phase 1b/2 trial to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and antitumor activity of oral vecabrutinib in adult pts with relapsed/refractory advanced B-cell malignancies who must have received ≥2 prior regimens and progressed on therapy with a cBTKi where available as an approved indication. Prespecified dose levels are 25 to 500 mg PO BID. Patients continue to receive vecabrutinib until time of progression or intolerable toxicity. The safety period for DLT assessment is Cycle 1 (4 weeks). Activity is monitored throughout study treatment and for survival. Molecular profiles, PK, and PD are also evaluated. Results: To date, 27 pts (chronic lymphocytic leukemia [CLL], n=21; mantle cell lymphoma [MCL], n=2; Waldenström's macroglobulinemia [WM], n=3; marginal zone lymphoma (MZL), n=1) have been treated (Cohort 1, 25 mg BID, n=3; Cohort 2, 50 mg BID, n=10; Cohort 3, 100 mg BID n=7, Cohort 4, 200 mg BID n=4, Cohort 5, 300 mg BID n=3): median age 66 yrs (range: 47-77), 96% ECOG PS 0-1, 73% male, median prior regimens 4 (range: 2-9) all including a cBTKi (23 pts ibrutinib, 4 pts acalabrutinib). At screening, 76% (19/25) had mutated or deleted TP53, 48% (12/25) had BTK C481 mutations and 20% (5/25) had phospholipase C gamma 2 (PLCg2) mutations. BTK C481 mutation was found in 11 CLL pts (C481S n= 8 variant allelic frequency [VAF] 7-93%, C481R n=2, [VAF 49%, 77%], C481P n=1 [VAF 28%]) and in one pt with WM (C481S [VAF 8%]). One CLL pt had both BTK C481S (VAF 20%) and T474I (gatekeeper residue, VAF 32%) mutation. Five pts (3 CLL, 1 WM and 1 MZL) had PLCg2 mutations; only one of the CLL pts had an activating PLCg2 mutation (S707F; VAF 8%). Overall, NGS on a panel of 128 genes known to be recurrently mutated in lymphoid malignancies detected a median of 5 mutations/pt; the most common mutated genes were SF3B1 (24%), NOTCH1 and ATM (20% each). Safety: the MTD has not been reached through Cohort 4. Adverse Events (AEs) are available for 24 pts; the most common all-grade AEs were anemia (37.5%), headache, neutropenia and night sweats (each 25%). Drug-related Grade 3 AEs occurred in 3 pts, all from Cohort 2: increased ALT, neutropenia and worsening anemia (all in 1 pt), and leukocytosis (2 pts). Cohort 2 was expanded per protocol due to a DLT (insufficient doses received due to Grade 3 drug-related ALT increase). There were no drug-related serious AEs. Stable disease (investigator assessed) was seen in 4 pts with CLL, 3 of whom had BTK C481S mutation (Cohort 1, n=1, Cohort 2, n=2, Cohort 3, n=1); these pts remained on treatment 72->196 days. One CLL BTK C481S pt remains on treatment and in Cycle 7 was dose-escalated from 100 to 200 mg BID; two CLL pts with BTK C481S (50 mg, 100 mg BID) showed improvement in B-symptoms and decreased tumor burden (-47%, -16% SPD change). Two pts with CLL (200 mg BID) are in Cycle 3, one with BTK C481S, T474I and one with PLCG2 S707F; 3 pts (300 mg BID; 2 CLL, 1 MZL) are currently in Cycle 1. Cycle 1 Day 8 vecabrutinib median steady-state Cmin values increased with dose: 75 ng/mL (Cohort 1, n=3), 451 ng/mL (Cohort 2, n=10), 873 ng/ml (Cohort 3, n=4) and 1124 ng/ml (Cohort 4, n=4) indicating that doses of ≥200 mg BID should result in consistent and high levels of BTK inhibition (Neuman ASH 2017). PD assessments (BTK phosphorylation; changes in chemokines) confirmed on-target inhibition of BTK. Of 20 pts evaluated, 12 had interpretable pBTK data with decreases seen as early as 1 hour post-first dose (avg 81%; range 37-100%) and sustained inhibition at end of Cycle 1 (avg 80%; range 48-100%). Most pts who completed cycle 1 had a decrease in at least 2 of 3 cytokines (CCL2, CCL3, CCL4). Conclusions: To date, vecabrutinib safety profile in 25-200 mg BID cohorts was acceptable with evidence of clinical activity. Dose levels are under investigation that may result in greater clinical activity in pts whose disease remains adequately sensitive to BTK inhibition. Evaluation of the 300 mg BID cohort is ongoing and updated trial results will be presented. Disclosures Allan: Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Sunesis: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Wierda:Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding. Pinilla Ibarz:Bayer: Speakers Bureau; Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. O'Brien:Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Eisai: Consultancy. Sharman:AstraZeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy; Acerta Pharma: Research Funding; Astra Zeneca: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Sound Biologics: Consultancy; TG Therapeutic: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Atara Biotherapeutics: Consultancy. Davids:AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ward:Sunesis Pharmaceuticals: Consultancy. Acton:Sunesis Pharmaceuticals: Consultancy. Taverna:Sunesis Pharmaceuticals: Employment. Fox:Sunesis Pharmaceuticals: Employment. Furman:Acerta Pharma: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Verastem: Consultancy. Brown:Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy.

Background: SNS-062 is a potent, noncovalent (reversible) BTK inhibitor in development for B-cell malignancies and other cancers. SNS-062 has the potential for activity in patients whose cancers are sensitive to BTK inhibition, as well as those that are resistant to ibrutinib through acquisition of a BTK Cys481Ser mutation. In vitro studies have demonstrated that SNS-062 antitumor activity in cells with the mutation is unaffected (Binnerts et al, EORTC 2015, Abstract C186), in contrast to the substantially reduced activity seen with ibrutinib and acalabrutinib. This study was designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SNS-062 in healthy subjects. Methods: This was a phase 1a, first-in-human, randomized, double-blind, placebo-controlled, sequential-group, single-dose study conducted in 3 stages. In stage 1, four sequential cohorts of 8 subjects were randomly assigned to receive ascending SNS-062 dose levels (50, 100, 200, and 300 mg; n=6, 3 male, 3 female) or placebo (n=2, 1 male, 1 female) as a single dose administered orally. The primary endpoint was safety, assessed by adverse events (AEs), laboratory parameters, and cardiac monitoring. Secondary endpoints included PK parameters and PD parameters (inhibition of phosphorylation BTK [pBTK] as determined by ELISA in whole blood lysates). Stages 2 and 3 were designed to evaluate the effects of food and CYP3A4 inhibition, respectively, on the PK of SNS-062. Results: In stage 1 (n=32), the median age was 55 years (range: 22-64) among those who received SNS-062 (n=24) and 42.5 years (range: 29-65) among those who received placebo (n=8). Treatment-emergent AEs (TEAEs) were reported for 8 (33%) subjects who received SNS-062 and for 3 (38%) subjects who received placebo. TEAEs reported for subjects who received SNS-062 included headache (n=5) and nausea, constipation, bronchitis, fatigue, orthostatic hypotension, and supraventricular tachycardia (n=1 each) without obvious evidence of dose dependency. AEs in the placebo group included headache (n=2), nausea (n=2), and diarrhea (n=1). AEs were all reported as Grade 1 except for 1 subject (who received 300 mg SNS-062) who experienced Grade 2 headache and fatigue. No Grade 3 or higher AEs and no serious AEs were reported. SNS-062 was rapidly absorbed (median Tmax: 1 hour [range: 0.5-3.0 hours]). SNS-062 concentrations declined in a multiphasic manner. Exposure increased approximately proportional to dose. Mean PK parameters for each cohort are shown in the Table. SNS-062 demonstrated rapid and near complete inhibition of pBTK at all dose levels. Stages 2 and 3 are in progress and results of the completed study will be reported at the meeting. Conclusions: The observed safety, PK, and PD profiles of SNS-062 in this phase 1a study in healthy subjects support further clinical investigation. This study continues to evaluate the effects of food and CYP3A4 inhibition on SNS-062 PK. Mean SNS-062 exposure at 50 mg, the lowest dose level studied, exceeded those reported for ibrutinib (Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, LLC; 2016) and acalabrutinib (Byrd et al, N Engl J Med 2016;374:323:32) when those drugs are administered at recommended dose levels. The extent of SNS-062 exposure and duration of pBTK inhibition are encouraging and support twice-daily dosing in a planned phase 1b/2 study in patients with advanced B-cell malignancies with and without the BTK Cys481-Ser mutation. This study was sponsored by Sunesis Pharmaceuticals. Disclosures Neuman: Puma Biotechnology: Employment; Sunesis Pharmaceuticals: Employment. Ward:Sunesis Pharmaceuticals: Consultancy, Employment. Arnold:Sunesis Pharmaceuticals: Consultancy. Combs:Sunesis Pharmaceuticals: Consultancy. Gruver:Sunesis Pharmaceuticals: Employment. Hill:Sunesis Pharmaceuticals: Employment. Miller:Sunesis Pharmaceuticals: Consultancy. Fox:Amphivena Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Patent #9212225; Bispecific CD33 and CD3 Binding Proteins; Sunesis Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties: Patent Application #20150202189; Methods of Using SNS-595 for Treatment of Cancer Subjects with Reduced BRCA2 Activity.

Abstract. The objective of this study was to evaluate the clinical response of locally advanced breast cancer (LABC) to neoadjuvant (NA) chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and to study the role of docetaxel in patients who fail to respond to first-line chemotherapy. Patients were enrolled who had primary tumours without distant metastasis that were too extensive for conservative surgery. All underwent NA chemotherapy for breast cancer and thereafter surgery and/or radical radiotherapy. NA chemotherapy with FEC was administered to 88 patients between February 1998 and June 2005. A median of 6 cycles of FEC (range 1-8) was given, followed in 21 cases by a median of 4 cycles (range 2-6) of docetaxel. Where clinically established, with FEC the clinical complete response (cCR) was 22/81 (27%), clinical partial response (cPR) 41/81 (51%), clinical stable disease (cSD) 18/81 (22%). In patients where the response to FEC was regarded as insufficient, docetaxel was given. Response rates were cCR 3/21 (14%); cPR 10/21 (48%), cSD 8/21 (38%). There were 11 cases of pathological complete response (pCR), 9 in the FEC-only group and 2 in the docetaxel group. Following chemotherapy 49 (56%) patients underwent mastectomy, 32 (36%) breast conserving surgery and 5 (6%) radical radiotherapy, giving a breast conservation rate of 42%. Two patients died before receiving surgery or radical radiotherapy. The results show that neoadjuvant FEC is a reasonable NA therapy in breast cancer and that docetaxel is effective in FEC refractory cases. Only 8 of 81 (10%) assessable patients did not respond to any chemotherapy, giving an overall clinical response rate of 90%, which is comparable to studies in which taxanes were given irrespective of response to preceding therapy with antracycline including regimes. IntroductionNeoadjuvant chemotherapy is regarded as a useful procedure in the management of locally advanced (i.e. stage III) or large (≥3 cm) breast cancers. The aim of this approach is to induce tumour shrinkage in order to increase the possibility of breastconserving surgery in patients with potentially operable tumours and the response to neoadjuvant chemotherapy can be used to select subsequent adjuvant cytotoxic therapy.Studies comparing adjuvant with neoadjuvant chemotherapy, without adjustment on the basis of response, have found higher rates of breast conserving surgery but no significant differences in terms of disease-free or overall survival have been observed (1).Many studies have been published with various chemotherapy regimens, but we reasoned that the optimal choice of regimen would be to use as first-line the regimen we use as adjuvant therapy, i.e. the FEC regimen, and in those who fail to respond, switch to our second-line, non-cross-resistant therapy of choice, docetaxel. We felt that this approach would have two advantages: firstly, we could determine which patients were sensitive to one or other regimen, which would then be expected to inform about optimal adjuvant chemotherapy; ...